Mazindol combination in the treatment of attention-deficit/hyperactivity

ABSTRACT

The present invention relates to the field of human health, and more particularly to the treatment of attention deficit/hyperactivity disorder (ADHD) with mazindol. The latter can be administered as monotherapy or in combination with one or more compounds, including psychostimulants, for the indication of ADHD and associated or co-morbid symptoms.

The present invention relates to the field of human health, and moreparticularly the treatment of attention-deficit/hyperactivity disorder(ADHD) with mazindol. The latter can be administered as monotherapy orin combination with one or more compounds, including psychostimulants,for the indication of ADHD and associated or co-morbid symptoms.

ADHD is a behavioural disorder that constitutes one of the mostfrequently encountered patterns in child and adolescent psychopathology.Its prevalence is estimated at 2% to 5% in the general population ofchildren of school age.

On a clinical level, this disorder combines inattention, impulsivity andmotor hyperactivity unsuited to the child's environment. Badly organisedand thoughtless, these children sometimes end up not following in class.Excessive motor agitation, incompatible with social relations andsometimes even leading to being prematurely taken. out of school, isprobably the symptom that will lead the parents to consult a specialist.

The stimulating substances used, and commonly accepted in thepharmacological treatment of ADHD, in particular in children, belong toseveral pharmacological classes: psychostimulants (amphetamine,methylphenidate, bupropion), eugregorics (Modafinil, Adrafinil), andinhibitors of mono-amine oxydase B (selegiline).

The most used and best known are:

methylphenidate (MPH) is the reference treatment of ADHD in children,adolescents and adults. It is above all a psychostimulant known for itsstimulating properties. Apart from its dopaminergic stimulating action,on the release of noradrenaline and dopamine, by inhibition andrecapture, MPH has no effect on the postsynaptic noradrenergic alpha-1receptors (modification of sensitivity).

amphetamine (D,L-amphetamine) has an action on the extra-vesicularrelease of noradrenaline and dopamine and therefore inhibits any form ofstorage. Because of potential misuse, and undesirable peripheral effects(tachycardia, HTA, agitation, insomnia) its medication remains verylimited and non-authorised in the majority of countries in Europe.

Modafinil, the authorisation of which for the treatment of ADHD inchildren has just been granted recently in the United States (2005), isa stimulating (eugregoric) medication whose action mechanism, which iscomplex, is imperfectly known. Unlike MPH and amphetamines, Modafinildoes not cause dependency or habituation. Its prescription is at thepresent time limited in France to the treatment of narcolepsy andidiopathic hypersomnia.

Atomoxetine, a selective inhibitor of the recapture of noradrenaline,and a dopaminogenic stimulant (by inhibiting recapture at thepre-frontal cortex), has demonstrated efficacy and good tolerance inADHD in children and adults (Spencer et al, 1998; Popper 2000; Biedermanet al, 2002). It has recently been authorised for marketing in theUnited States (FDA, November, 2002).

others: bupropion, caffeine, selegiline, etc.

Bupropion, a catecholamine uptake inhibitor, and an antidepressant, isalso a potential competitor in the treatment of ADHD.

Selegiline, a mono-oxidase uptake inhibitor, also has pharmacologicalproperties close to those of amphetamines. Its stimulating action in thetreatment of ADHD is known and its advantage in this use is possible.

Thus the improvement of motive hyperactivity by dopaminergenicpsychostimulants is often very significant, but neverthelessinsufficient.

This is because the stimulating substances used or which could be usedin the treatment of ADHD, in particular psychostimulants such asmethylphenidate or amphetamines, often have a short plasmatic half-life,which involves the appearance of “on-off” effects, that is to say acoming-off effect that is accompanied by a “symptom rebound” effectafter a few hours and is responsible for a worsening of the symptoms inthe last part of the night, and detrimental to the quality of fallingasleep.

In addition, some of these substances are metabolised in the organismand therefore present a toxic risk for the patient.

In addition, some of the medications administered in the treatment ofADHD are not suited to particular administration to children, especiallybecause of excessive size of the tablets or the administration of themedications several times a day.

In addition, certain particular symptoms such as insomnia, difficultiesin falling asleep, waking during the night, possibly due to excessivenocturnal motive agitation, as well as additional disorders such asinattention, impatience and impulsivity, seem to resist any form oftreatment [Chervin et al, Associations between symptoms of inattention,hyperactivity, restless legs, and periodic leg movements. Sleep 2002 15;25(2):213-8; Gruber et al, instability of sleep patterns in childrenwith attention-deficit/hyperactivity disorder. J Am Acad Child AdolescPsychiatry. 2000; 39(4):495-501].

There therefore exists a real need to develop new treatments for ADHDthat make it possible to obtain results superior to those obtained withcurrent treatments based on psychostimulants and in particular to beable to treat the symptoms that resist current treatments, without anycoming-off effect or rebound of the symptoms and presenting limitedtoxic risk. Treatments intended more particularly for children areadvantageously sought. This is the aim of the present invention.

Entirely fortuitously, studies have now shown that mazindol could beused for the preventive and curative treatment of ADHD with significantresults, without the previously mentioned drawbacks of the othersubstances, in particular certain psychostimulants.

Mazindol has the following chemical formula:

5-(4-chlorophenyl)-2,5-dihydro-3 H-imadazo [2,1-a]isoindol-5-ol

Mazindol is considered, in current medication classifications, as aphsycoanaleptic and anorexigenic medication, but also as giving rise towakefulness, currently not authorised in France, or only authorised byTAU (temporary authorisation for use) in obesity and narcolepsy. It isan advantageous chemical compound for dealing with malfunctioning ofwakefulness mechanisms.

The essential pharmacological action of mazindol, in all speciesstudied, in healthy animals and in humans, is hypothalamic, on theappetite-regulating dopaminogenic centres (Hadley, 1972). Its principalmetabolism is urinary (¾ urine, ¼ faeces).

Mazindol is a non-amphetamine compound because of Its tricyclic chemicalstructure. It offers a pharmacological profile very close to that ofamphetamines without reproducing the secondary effects thereof. Thus,unlike amphetamine molecules, mazindol increases motor activity only inrelation to extension of the duration of wakefulness and does not causecardiovascular modifications or stereotypes (Nadler, 1972).

In addition, in animal toxicology studies, the toxic potential ofmazindol has proved to be very low. This is because mazindol presents alimited toxic risk since the metabolites of mazindol are excreted in theurine. In particular:

no carcinogenic effect;

no mutagenic effect;

no toxicology effect in reproduction were observed.

In addition, mazindol has a long plasmatic half-life time, greater thanone day, which avoids the appearance of coming-off effects, andtherefore an effect of “symptom rebound” at the end of the day.

In fact, after single or repeated oral administration, mazindol isabsorbed with a tmax of 2-4 hours. Taking food concomitantly is liableto delay absorption (by approximately 1 hour), but does not modify thetotal quantity absorbed. The plasmatic half-life time is reached after33-55 hours.

The pharmacokinetics is linear (independent of the dose) for doses ofbetween 1 mg/day and 4 mg/day, and 75% of the dose is still“plasmatically” effective 24 hours after taking.

In addition, mazindol (Teronac®) tablets are small and therefore do notpose any problem in administration. For pharmacokinetic reasons, alreadycited, mazindol is administered only once a day, which limitsconstraints for the patient, and in particular in the special case ofchildren for the school, which is often requested to perform the middayadministration.

Mazindol has for more than 30 years been the subject of many doubleblind control studies against a placebo on the treatment of obesity inadults. Studies in the treatment of narcolepsy and hypersomnia arelimited. On the other hand, safety in use in the short, medium and longterm in the treatment of excessive daytime somnolence associated withnarcolepsy and idiopathic hypersomnia is relatively well documented forthe time (Shindler et al, 1985).

Mazindol has in these two disorders (narcolepsy and hypersomnia) becomea TAU (Temporary Authorisation for Use) treatment by third intentionthat significantly improves the quality of life of the patient havingdifficulty in keeping awake.

The object of the present invention is therefore the use of mazindol forthe preparation of a medication intended for the preventive and/orcurative treatment of attention-deficit/hyperactivity disorder (ADHD) orat least one of its symptoms, in a patient in need of such treatment.

In the context of the present invention, ,the diagnosis ofattention-deficit/hyperactivity disorder (ADHD) is based on the clinicalcharacteristics defined by the international classification, DSM/IV(Diagnostic and Statistical Manual of Mental Disorders, 4th ed, 1994).

The criteria of DSM-IV includes three dimensions (inattention,impulsivity and hyperactivity), normal intellectual efficiency (IQ>80,with an age between 5 and 12 years) and having isolated iron deficiency,but not anaemic, that is to say having a normal haemoglobin level. Theexpression “iron deficiency” means hypoferrinaemia without significantmodification to the serum concentration of soluble transferrinreceptors.

The patient according to the invention is chosen from among a newbornbaby, a child, an adolescent and an adult. According to a preferentialembodiment, it ie a case of a child aged approximately 5 to 12 years,and/or for an adolescent. The patient according to the inventionadvantageously suffers iron deficiency, but is not anaemic. Ferritindeficiency can be measured in the serum, but also in all otherbiological fluids such as the cerebrospinal fluid.

A ferritin deficiency corresponds to a serum concentration of ferritinin the adult patient of less than approximately 50 μg/litre. Thishypoferritinaemia may reach ferritin concentrations of less thanapproximately 40 μg/l, or even less than approximately 35 μg/l, lessthan 30 μg/l, less than 20 μg/l, less than 15 μg/l, or even less than.approximately 10 μg/l. The techniques of determining serum ferritin arewell known to persons skilled in the art. The immunoenzymatic method(IMX ferritin kit, Abbot Laboratories) can be cited.

The patient according to the invention also has a normal serumconcentration of receptors soluble to transferrin. Transferrin isinvolved in the acquisition of iron by the cells of the organism; thisacquisition is controlled by the number of transferrin receptorsexisting on the cell. surface. The concentration of these receptors canbe evaluated by techniques known to persons skilled in the art such asnephelemetry (Ruivard et al. 2000 Rev Med Interne 21: 837-843). A normalrange of concentration of receptors soluble to transferrin is 2.0-4.50mg/l for men and 1.80-4.70 mg/l for women (see RsTF kit Ref 2248315 fromRoche).

The compounds or compositions according to the invention can beadministered in various ways and in different forms. Thus they can beadministered systemically, orally, anally or parentally, in particularby inhalation or injection, such as for example by intravenous,intramuscular, subcutaneous, transdermal or intra-arterial method.Preferably it is orally.

For injections, the compounds are generally packaged in the form ofliquid suspensions, which may be injected by means of syringes orperfusions for example. In this regard the compounds are generallydissolved in saline, physiological, isotonic, buffer, etc., solutions,compatible with pharmaceutical usage and known to persons skilled in theart. Thus the compositions may contain one or more agents or vehicleschosen from dispersants, solubilisers, stabilisers, preservatives, etc.Agents or vehicles that can be used in liquid and/or injectableformulations are in particular methylcellulose, hydroxymethylcellulose,carboxymethylcellulose, polysorbate 80, mannitol, gelatine, lactose,vegetable oils, acacia, etc.

The compounds can also be administered in the form of gels, oils,tablets, suppositories, powders, capsules, aerosols, etc, possibly bymeans of galenic forms or devices providing prolonged and/or delayedrelease. For this type of formulation, use is advantageously made of anagent such as cellulose, carbonates or starches.

“ADHD symptom” designates in particular attention disorders such asinattention, impulsivity, impatience, oppositional disorders, but alsodaytime or night-time motor hyperactivity, restless legs syndrome, andinsomnia.

Insomnia designates

a. onset insomnia that is characterised by difficulties in fallingasleep;

b. maintenance insomnia that is characterised by night-time motorhyperactivity and waking up during the night, and

c. psychopathological insomnia, generally chronic and generally linkedto anxiety, stress and depressive episodes.

According to another aspect of the present invention, mazindol is usedin combination with iron as a combination product for simultaneous,separate or sequential use.

According to a preferred method of use, the iron is used as a supplementwith the patient before the administration of mazindol.

Within the meaning of the present invention, “iron” means iron. in theform of an iron atom, iron salt or organic iron, or any formulationcontaining iron that is pharmaceutically acceptable. By way of anon-exhaustive list, the pharmaceutically acceptable iron salt isselected from ferrous salts and ferric salts, preferably from ferricammonium citrate, ferric pyrophosphate, ferrocholinate, ferrousabscorbate, ferrous aspartate, ferrous chloride, ferrous sulphate,ferrous tartatrate, ferrous fumatrate, ferrous gluconate, ferrousgluceptate, ferrous sulphate glycine, ferrous lactate, ferrous oxalateand ferrous succinate.

According to a preferred embodiment of the invention, the iron salt isferrous sulphate, and preferably gastro-protected ferrous sulphate.

Alternatively, the pharmaceutical acceptable iron is in the form ofdextran iron, sucrose iron, poly-maltose iron, or sorbitol iron. Whenthe iron is in the form of pharmaceutically acceptable organic iron, itis preferably iron biglycinate, iron glycinate or iron proteinsuccinylate.

According to a preferred embodiment, the use of mazindol possibly inassociation with the iron according to the invention is implemented incombination with at least one compound selected from psychostimulants,as a combination product for simultaneous, separate or sequential use.

Psychostimulant compounds designate dopamine and/or noradrenaline uptakeinhibitors and agonists of catecholamines. Among these, the followingcan be cited non-exhaustively:

1) psychostimulant compounds: methylphenidate (speciality Ritalin,Concerta, Equasym), modafinil (Sparlon, Modiodal, Provigil), atomoxetine(Strattera), and amphetamines such as d-amphetamine, dexadrine anddexamphetamine.

2) L-Dopa: Modopar, Sinemat

3) selective dopamine agonists: pramipexole (Sifrol, Mirapex),ropinirole (Requip, Adartrel), lisuride, pergolide, cabergoline, etc.

The role of iron with regard to the central nervous system is oftenreported in fundamental neurophysiopathology as clinical. Functionalintellectual asthenia, chronic fatigue syndrome, or converselypsychomotive instability and irritability may be the consequence of irondeficiency (Lozoff, 1989 Adv Pediatr 1989; 6:331-59). The role of ironin the physiopathology of neurological ailments, and in particular inidiopathic Parkinson's disease, has been known for more than thirtyyears. The evidence of an increase in iron in particular in certaincerebral structures (e.g. dentate nucleus) in rare neurodegenerativepathologies (e.g. Friedreich's ataxia) is also known. More recently, therole of transferrin receptors in certain neuropathological processes hasjust been documented (Marder F et al, 1998 Neurology 50, 4:1138-40). Anincrease in number of transferrin receptors in cells of the endotheliumof the cerebral capillaries could be responsible for the accumulation ofbasal ganglia (globus pallidus, substantia nigra, red nucleus anddentate nucleus). A malfunctioning of the transferrin receptors byhyperplasia (increase in the number of receptors) at a central levelwould explain the accumulation of iron in certain structures involved inphenomena of neuroclegenerescence. On the other hand, a reduction inthese receptors would contribute to protecting the central nuclei fromthe phenomenon. On the assumption of a decrease in plasma ferritin inADHD physiopathology, a physiological increase in the transferrinreceptors should occur, as occurs normally in cases of anaemia, in ordernot to put the cerebral structures in iron deficiency. On the otherhand, an absence of response (an absence of increase in the number oftransferrin receptors) would lead to a cerebral iron reduction and wouldbe compatible with dopamine malfunctioning by reducing its synthesisand/or stimulating the dopaminergic receptors. The present inventiontherefore also concerns the use of mazindol, optionally in associationwith iron or one of its pharmaceutically acceptable salts, and/or apsychostimulant for the preventive treatment of a newborn, infant,adolescent or young adult patient caused to develop a neurodegenerativepathology at an adult age, characterised in that the said newborn,infant, adolescent or young adult patient has at least the followingsymptoms:

ferritin deficiency, so that the serum concentration of ferritin is lessthan 50 μg/l;

a normal serum concentration of receptors soluble to transferrin;

attention-deficit/hyperactivity disorder, or at least one of itssymptoms.

Preferably the said patient is a child with an IQ>80, aged betweenapproximately 5 and 12 years and non-anaemic.

Preferably the said neurodegenerative pathology is Parkinson's disease,cerebellar ataxia, Friedreich's ataxia, Alzheimer's disease,Huntingdon's chorea or amyotrophic lateral sclerosis. More particularly,it is Parkinson's disease.

In particular, when mazindol is used in association with ferroussulphate, the quantity of ferrous sulphate administered to the patienton a daily basis is between 0.1 mg and 10 mg, preferably between 100 mgand 2 g per day, preferably approximately 500 mg, in one or more doses.

More particularly, according to the present invention, the patientsundergo iron supplementation, in particular ferrous sulphate, for 12weeks and the treatment with mazindol for 12 weeks.

The dosage corresponds to a daily dose of mazindol preferably between 1and 2 mg (recommended doses in the treatment of narcolepsy in adults).

The criteria for evaluating the efficacy of the treatment ofattention-deficit/hyperactivity disorder by mazindol optionally inassociation with iron and/or a psychostimulant in the treatment ofattention-deficit/hyperactivity disorder according to the presentinvention are the reduction (>30%) in the rating scale severity scorefor attention-deficit/hyperactivity symptoms AHD-RS (after 12 weeks oftreatment, and an improvement in severity scores for Conner's Parentquestionnaire (CPRS), Conner's Teacher questionnaire (CTRS) and CGI(clinical global impressions). Subjective somnolence is assessed usingthe CASS scale (child and adolescent somnolence scale). The quality offalling asleep is assessed by means of the restless legs syndromeseverity scale.

Finally, the present invention also concerns a pharmaceuticalcomposition comprising pharmaceutically acceptable excipients andmazindol for the preventive and/or curative treatment of ADHD or one ofits symptoms.

According to the present invention, the composition may also compriseiron or one of its pharmaceutically acceptable salts and/or apsychostimulant.

REFERENCES

Biederman J, Swanson J M, Wigal S B, Kratochvil Boefiner S W, Earl C Q,Jiang J, Greenhill L. Efficacy and safety of modafinil film-coatedtablets in children and adolescents with attention-deficit/hyperactivitydisorder: results of a randomised, double-blind, placebo-controlled,flexible-dose study, Pediatrics 116: e777 2005

Biederman J, Heiligenstein J H, Fares D E, Galli. N, Dittmann R, EmslieG J, Kratochvil C J, Laws H F, Schuh K J, Efficacy of atomoxetine versusplacebo in school-age girls with attention-deficit/hyperactivitydisorder. Pediatrics 110(6):75; 2002

Busby K, Firestone P, Pivik RT—Sleep pattern in hyperkinetic and normalchildren. Sleep, 4, 366-83; 1981

Carskadon M A, Dement W C—Sleepiness in the normal adolescent. In: Sleepand its disorders in children. New York, Raven; 1987

Carskadon M A, Dement W C—The multiple sleep latency test: what does Rmeasure? Sleep, 5, 567-72; 1982

Carskadon M A, Dement W C, Mitler M M, Roth T, Westbrook P R, KeenanS—Guidelines for the Multiple Sleep Latency Test (MSLT): a standardmeasure of sleepiness. Sleep 9:519-24; 1986

Chervin R D, Archbold K H, Dillon J E, Pituch K J, Panahi P, Dahl R E,Guilleminault C, Associations between symptoms of inattention,hyperactivity, restless lege, and periodic leg movements. Sleep 15;25(2):213-8; 2002

Corkum P, Moldofsky H, Hogg-Johnson, Humphries T, Tannock R—Sleepproblems in children with attention-deficit/hyperactivity disorder:impact of Subtype, comorbidity, and stimulant medication. J Am AcadChild Adolesc Psychiatry 38, 1285-93; 1999

Corkum P, Tannock R, Moldofsky H—Sleep disturbances in children withattention-deficit/hyperactivity disorder. J Am Acad Child AdolescPsychiatry 37, 6, 637-46; 1998

Cortese S, Konofal E, Lecendreux M, Arnuif I, Mouren M C, Darra F, DallaBernardine B. Restless legs syndrome and attention-deficit/hyperactivitydisorder: a review of the literature. Sleep. 2005; 28(8):1007-13.

Golan N, Shahar E, Ravid S, Pillar G. Sleep disorders and daytimesleepiness in children with attention-deficit/hyperactivity disorder.Sleep. 15; 27:261-6; 2004

Greenhill L L, Puig-Antich J, Goetz R, Hanlon C—Sleep architecture andREM sleep measure in prebutertal children with attention deficitdisorder with hyperactivity. Sleep 6, 91-101; 1983

Hadier A J, mazindol, a new non-amphetamine anorexigenic agent. J ClinPharmacol New Drugs. 12:453-8. 1972

Kaplan B J, McNicol J, Conte R A, Moghadam H K. Sleep disturbance inpreschool aged hyperactive and nonhyperactive children. Pediatrics 80:839-44; 1987

Konofal E, Lecendreux M, Bouvard M and Mouren-Siméon M-C. High levels ofnocturnal activity in children with ADHD; a video analysis. PsychiatryClin Neurosci 55, 2, 97-103; 2001

Konafal E, Lecendreux M, Mouren-Simeon M-C. Sleep in children withattention-deficit/hyperactivity disorder: a restatement on sleepstudies. Ann Med Psychol 160:105-17; 2002

Konofal E, Lecendreux M, Arnulf I, Maurer M C. Iron deficiency inchildren with attention-deficit/hyperactivity disorder. Arch PediatrAdolesc Med. 2004; 158(12) :1 113-5

Konofal E, Cortese S, Lecendreux M, Arnulf I, Mouren M C. Effectivenessof Iron supplementation in a young child withattention-deficit/hyperactivity disorder. Pediatrics 2005; 116(5).

Konofal E, Cortese S. Resless legs syndrome andattention-deficit/hyperactivity disorder.

Ann Neurol. 2005; 58(2):341-2

Lecendreux M, Konofal E, Bouvard M, Falissard B, Mouren-SimeoniM-C—Sleep and alertness in children with ADHD. J Child PsycholPsychiatry 41, 6, 803-12; 2000

Mick B, Biederman J, Jetton J, Faraone S V. Sleep disturbancesassociated with attention-deficit/hyperactivity disorder: the impact ofpsychiatric comorbidity and pharmacotherapy. J Child AdolescPsychopharmacol Fall 10, 3:223-31; 2000

Palm L, Persson E, Bjerre L, Elmqvist O—Sleep and wakefulness inpreadolescent children with deficits in attention, motor control andperception. Acta Paediatr 81, 618-24; 1992

Picchietti D L, Walters As—Restless legs syndrome and periodic limbmovement disorder in children and adolescents: comorbidity withattention-deficit/hyperactivity disorder. Child Adolesc. Psychiatry ClinN Am 5, 729-40; 1996

Platen M J R, Vela Bueno A, Espinar Sierra J, Kales S—Hypnopolygraphicalterations in attention deficit disorder (ADD) children, Intern JNeurosci 53, 87-101; 1990

Popper C W—Pharmacologic alternatives to psychostimulants for thetreatment of attention-deficit/hyperactivity disorder. Child AdolescPsychiatr Clin N Am 9, 3, 605-46; 2000

Rugine T A, Copley T C. Effects of modafinil in children withattention-deficit/hyperactivity disorder: an open study. J Am Acad ChildAdolesc Psychiatry 40(2):230-5; 2001

Schindler J, Schachter M, Brincat S, Parkes J D. Amphetamine, mazindol,and fencamfamin in narcolepsy. Br Med J. 20; 1167-70; 1985

Trommer B L, Hoeppner J B, Rosenberg R S, Armstrong K J, Rothstein J A.Sleep disturbance in children with attention deficit disorder. AnnNeurology 24: 322; 1988

Walters A S, Mandelbaum D E, Lewin D S, Kugler S, England S J, Miller MDopaminergic therapy in children with restless legs/periodic limbmovements in sleep and ADHD. Dopaminergic Therapy Study Group. PediatrNeurol 22, 3, 182-6; 2000

Weinberg A S, Brumback R A—Primary disorder of vigilance; a novelexplanation of inattentiveness, daydreaming, boredom, restlessness, andsleepiness. J Pediatr 116, 720-5; 1992

Weinberg W A, Harper C R—Vigilance and its disorders. Neurol. Clin 11,59-78; 1993

Weis M, Murray C, Weiss G. Adults with attention-deficit/hyperactivitydisorder: current concepts. J Psychiatr Pract. 28, 99-111; 2002

10-15. (canceled)
 16. A pharmaceutical composition comprising apharmaceutically acceptable excipient and mazindol.
 17. The compositionof claim 16, further comprising iron or a pharmaceutically acceptablesalt thereof and/or a psychostimulant.